Testing marginal homogeneity against stochastic order in multivariate ordinal data.

SUMMARY: Many assessment instruments used in the evaluation of toxicity, safety, pain, or disease progression consider multiple ordinal endpoints to fully capture the presence and severity of treatment effects. Contingency tables underlying these correlated responses are often sparse and imbalanced, rendering asymptotic results unreliable or model fitting prohibitively complex without overly simplistic assumptions on the marginal and joint distribution. Instead of a modeling approach, we look at stochastic order and marginal inhomogeneity as an expression or manifestation of a treatment effect under much weaker assumptions. Often, endpoints are grouped together into physiological domains or by the body function they describe. We derive tests based on these subgroups, which might supplement or replace the individual endpoint analysis because they are more powerful. The permutation or bootstrap distribution is used throughout to obtain global, subgroup, and individual significance levels as they naturally incorporate the correlation among endpoints. We provide a theorem that establishes a connection between marginal homogeneity and the stronger exchangeability assumption under the permutation approach. Multiplicity adjustments for the individual endpoints are obtained via stepdown procedures, while subgroup significance levels are adjusted via the full closed testing procedure. The proposed methodology is illustrated using a collection of 25 correlated ordinal endpoints, grouped into six domains, to evaluate toxicity of a chemical compound.

Neurobehavioral evaluation in humans exposed to hydrocarbons: a new statistical approach.

BACKGROUND: Epidemiological researches showed a significant increase in the alterations of the cognitive and emotional sphere in subjects exposed to hydrocarbons. This paper deals with a study carried out on a group of male workers between the ages of 35 and 40, who had been working as external workers in a large refinery. METHODS: All the subjects worked in short shift rotation and were exposed to hydrocarbons during the loading of tank trucks. The response data reported by this investigation are compared to data of different male subjects who had also been working at the refinery for the same period of time, but as administrative day workers, and were certainly not exposed to the hydrocarbons. The nonparametric statistical analysis was carried out by a new nonparametric approach based on multivariate permutation tests. RESULTS: Results show a significant difference in the response to neurobehavioral tests. The exposed group showed behavioral tendencies towards anxiety and depression that the nonexposed group did not. CONCLUSIONS: The study shows that occupational exposure to hydrocarbons is associated with neurobehavioral modifications, and that the use of psychometric tests can be useful for monitoring the psychosomatic consequences by exposure to hydrocarbon microdoses.

Evaluation of the regional responsivity to ryanodine of human myocardium from patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathies.

The aim of the study was to compare the contractile response to ryanodine of human heart preparations taken from right and left ventricles of patients affected by idiopathic (IDCM) and secondary (SCM) end-stage dilated cardiomyopathies. Right and left ventricle myocardial strips were obtained from hearts of patients undergoing orthotopic heart transplantation and suspended in an oxygenated bath (T = 35 degrees C; stimulation frequency = 0.5 Hz). After an equilibration period, a cumulative dose-response curve for contractility (peak tension) was obtained with ryanodine (0.5, 1, 2, 4, 8, 16, 32, 64 microM). Basal contractility was not significantly different between right and left ventricles or between IDCM and SCM preparations. Ryanodine reduced peak myocardial tension but failed to completely suppress it, even at concentrations which achieved maximum effect. Ryanodine effect still persisted after a 45'-60' washout. The concentration-effect curves from IDCM right ventricle, IDCM left ventricle, SCM right ventricle and SCM left ventricle were compared: IDCM left ventricle was less sensitive to ryanodine than IDCM right ventricle and SCM left ventricle, while no difference was detectable between SCM left ventricle and SCM right ventricle. Thus, the overall sensitivity ranking was: IDCM left ventricle < IDCM right ventricle = SCM right ventricle = SCM left ventricle. IDCM left ventricle showed, in addition, a biphasic response with a shift from negative to positive inotropic effect at concentrations higher than approximately 10 microM. These findings indicate that the cardio-depressant effect of ryanodine, a drug which interferes with intracellular Ca release from the sarcoplasmic reticulum, differs quantitatively and qualitatively in IDCM left ventricle from both IDCM right ventricle and SCM left ventricle. This suggests that some specific alteration in the intracellular Ca signalling in IDCM exists and, from a methodological point of view, stresses the need for a "bi-ventricular" approach to studying biochemical and functional abnormalities of advanced congestive heart failure.

Hostility and irritable mood in panic disorder with agoraphobia.

Twenty patients suffering from panic disorder with agoraphobia were administered the hostility subscale of Kellner's Symptom Questionnaire and the irritability scales of Paykel's Clinical Interview for Depression and of Kellner's Anxiety Rating Scale before and after behavioral treatment of agoraphobia. A matched control group of normal subjects had the same assessments at two similar points in time. Hostility and irritable mood decreased and friendliness increased in patients with panic disorder after treatment; upon recovery, there were no significant differences in hostility between patients and controls, whereas such differences were striking during the illness. The results suggest that increased hostility and irritable mood may be symptoms of panic disorder and improve with the treatment of agoraphobia.

Mechanisms of change of panic attacks with exposure treatment of agoraphobia.

In vivo exposure homework was applied to a consecutive series of 30 outpatients suffering from DSM-IIIR panic disorder with agoraphobia. Assessment of the characteristics of panic attacks (the prodromal phase immediately preceding the attack, acute peak anxiety, and the residual phase immediately afterwards) was done by an independent rater before treatment, after six sessions and at the end of therapy (12 sessions). Twenty-five of the 30 patients completed treatment. All of them still reported panic attacks after six sessions, even though the characteristics of panic partially improved. At the end of therapy, panic attacks disappeared in 21 of the 25 patients (84%) and these gains were maintained to 1 year follow-up thereafter by the majority (81%) of subjects.

On a nonparametric combination method for dependent permutation tests with applications.

This paper deals with a combination method for dependent permutation tests, which is nonparametric with respect to the underlying unknown dependence structure. The method is based on a simulation or resampling procedure, conditional on the data, which provides a simulated estimate of the permutation distribution of any statistic. Applications to some unusual and quite complex testing problems are shown.

Losses, Hostility, and depression.

Forty outpatients with a primary unipolar major depression of recent onset and a matched control group of employees were administered the hostility scale of the Kellner Symptom Questionnaire, depression was rated with the Hamilton Rating Scale for Depression, and life events were recorded in a structured interview. In a subgroup of depressives who had not reported losses, there was an association of hostility and depression, whereas no such association was found in depressives who had reported losses. The findings are consistent with those of previous studies showing that hostility is largely limited to a subgroup of depressives. In a substantial proportion of the depressives, depression and hostility are independent affects.

Reference values for alanine and aspartate aminotransferase (ALT and AST) optimized by addition of pyridoxal phosphate.

The increases of the activity of aspartate and alanine transaminases observed in sera of healthy male and female subjects by addition of pyridoxal phosphate have been determined. The reference values of the activated reactions, distinguished by sex and age classes, are presented.

Flunitrazepam, a new benzodiazepine compound in general anaesthesia. Clinical and statistical considerations on the first thousand cases.

Flunitrazepam, a derivative of benzodiazepine was used for induction and maintenance of anaesthesia in 933 patients. The induction dose was from 1,786 to 2,053 mg. The total dose of 2-2.66 mg was sufficient for maintenance of hypnosis for about 2 hours. The undesirable side effects were very rare. The average time of hypnosis after a single dose of flunitrazepam was 50.1 sec. The sedative action of the drug lasted for some time after regaining of consciousness. In most patients there was no need for administration of analgetics during first 24 hours after the operation. The authors believe that surgical anaesthesia will greatly benefit from this drug.